Myelin, produced by the concentric wrapping of oligodendrocyte processes, is critical for the effective and timely communication between neurons in distant regions of the brain and spinal cord. During development, oligodendrocytes tailor the thickness of individual myelin sheaths to the diameter of their target axons to ensure appropriate neuronal function. The importance of myelination becomes obvious in demyelinating diseases such as multiple sclerosis (MS) where the eventual failure of myelin repair results in axonal degeneration and subsequent physical impairments. Furthermore, following episodes of demyelination and remyelination that occur early in the disease course of MS, the matching of myelin thickness to axon diameter fails potentially compromising function and leaving axons vulnerable to damage. How oligodendrocytes generate the appropriate thickness of myelin for an axon of defined size is unknown. A comprehensive understanding of the molecules and signaling pathways important for the generation of central nervous system (CNS) myelin is needed in order to design effective therapeutics tailored to enhance myelin repair in MS patients. Recently, we discovered that ERK1/2, key mediators of an evolutionarily conserved signaling pathway, are both necessary and sufficient for the expansion of the myelin sheath during development and following demyelinating injury in the adult mouse CNS. Based on these findings we hypothesize that ERK1/2 are critical regulators of CNS function through their oligodendrocyte-specific role in controlling myelin sheath growth. The proposed studies will use a series of transgenic mouse models with genetic loss or gain of ERK1/2 function to define the functional consequences of ERK1/2-mediated changes in myelin thickness. The use of an inducible system, where ERK1/2 is activated at specific stages of the oligodendrocyte-lineage, will allow us to tease apart both where and when activated ERK1/2 is most beneficial during myelin repair in two different models of demyelinating injury. Finally, we will test the role of important ERK1/2 interacting proteins to elucidate the molecular mechanisms and downstream targets of activated ERK1/2 important for myelin sheath growth. Defining the function of ERK1/2 in myelin sheath expansion will provide new insights to aid in the identification of novel therapeutic targets to promote myelin repair in patients with demyelinating diseases.